Current Pharmaceutical Design - Volume 13, Issue 1, 2007

Molecular imaging refers to the use of non-invasive imaging techniques to detect signals that originate from molecules, often in the form of an injected tracer, and observe their interaction with a specific cellular target in vivo. This technique is capable of measuring the biodistribution of minute concentrations of radio-labelled biomolecules in vivo and quantifying the molecular kinetic processes in which they participate. This technique can provide a wealth of information, which can facilitate the drug development process and the planning of therapy. This issue of Current Pharmaceutical Design highlights the capabilities of PET and SPECT in pre-clinical and clinical research and acknowledges the efforts from each contributor in putting this issue together. T.J. Wadas and co-workers [1] at the Mallinckrodt Institute of Radiology and the University of New Hampshire outline the use of copper isotopes in particular 64Cu in diagnostic imaging and radiotherapy. However, significant developments are required in the development of ligands that can form a stable complex with 64Cu for delivery into living systems. These advances are highlighted in this review. Y.S. Choe and K-H Lee [2] from the Samsung Medical Center review applications of targeted imaging of angiogenesis using molecular imaging and suitable radiotracers based on potential targets which include integrins, extracellular matrix, VEGF, activated endothelial cells and MMPs. Specific imaging of angiogenesis will help define the pathophysiology in living subjects and identify those patients likely to respond to antiangiogenic or angiogenic therapies and enable the efficacies of these therapies to be assessed. J. Lever [3] from the University of Missouri outlines the use of opioid receptors as drug targets and focuses on the status and use of radiotracers for imaging opioid receptors using molecular imaging. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development. T.L. Collier and co-workers [4] at Siemens Biomarker Solutions, Columbia University of Physicians and Surgeons and the University of Sydney outline the biological function and therapeutic potential of sigma receptors. Sigma receptors have recently been the target of drug development related to psychiatric disorders, cognitive enhancers, neuroprotective and antiamnesic actions. This review highlights what is known about these enigmatic sites and the use of molecular imaging in studying these receptors. References [1] Wadas TJ, Wong EH, Weisman GR, Anderson CJ. Copper Chelation Chemistry and Its Role in Copper Radiopharmaceuticals. Curr Pham Des 2007; 13(1): 3-16. [2] Choe YS, Lee K.-H. Targeted In Vivo Imaging of Angiogenesis: Present Status and Perspectives. Curr Pham Des 2007; 13(1): 17-31. [3] Lever JR. PET and SPECT Imaging of the Opioid System: Receptors, Radioligands and Avenues for Drug Discovery and Development. Curr Pham Des 2007; 13(1): 33-49. [4] Collier TL, Waterhouse RN, Kassiou M. Imaging Sigma Receptors: Applications in Drug Development. Curr Pham Des 2007; 13(1): 51-72.

Molecular imaging is an important scientific discipline that plays a major role in clinical medicine and pharmaceutical development. While several imaging modalities including X-ray computed tomography (CT) and magnetic resonance imaging (MRI) generate high-resolution anatomical images, positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer insight into the physiological processes that occur within a living organism. Of these two nuclear medicine imaging techniques, PET has advantages with respect to sensitivity and resolution, and this has led to the production and development of many positron emitting radionuclides that include non-traditional radionuclides of the transition metals. Copper-64 (t1/2 = 12.7 h, β+: 17.4%, E β+max = 656 keV; -:39%, E β-max = 573 keV) has emerged as an important positron emitting radionuclide that has the potential for use in diagnostic imaging and radiotherapy. However, 64Cu must be delivered to the living system as a stable complex that is attached to a biological targeting molecule for effective imaging and therapy. Therefore, significant research has been devoted to the development of ligands that can stably chelate 64Cu. This review discusses the necessary characteristics of an effective 64Cu chelator, while highlighting the development and evaluation of 64Cu-complexes attached to biologically-targeted ligands.

Angiogenesis, the process whereby new capillaries are formed by outgrowth from existing microvessels, is required for tumor growth and metastasis, and is also necessary for natural healing after ischemic injury. Because angiogenesis, excessive or deficient, underlies many pathological situations, there is a need for the development of noninvasive imaging to allow monitoring of angiogenesis related molecular events. Furthermore, specific imaging of angiogenesis would help define the pathophysiology of angiogenesis in living subjects, identify those patients likely to respond to antiangiogenic or angiogenic therapies, and enable the efficacies of these molecular therapies to be assessed. Herein, we review the targeted imaging of angiogenesis using nuclear medicine modalities (positron emission tomography; PET and single photon emission computed tomography; SPECT) and suitable radiotracers based on potential targets including integrin, extracellular matrix, VEGF and its receptors, activated endothelial cells, and matrix metalloproteinases.

As we celebrate the bicentennial of the isolation of morphine by Sertürner, opioids continue to dominate major sectors of the analgesic market worldwide. The pharmaceutical industry stands to benefit greatly from molecular imaging in preclinical and early clinical trials of new or improved opioid drugs. At this juncture, it seems fitting to summarize the past twenty or so years of research on molecular imaging of the opioid system from the viewpoint of drug discovery and development. Opioid receptors were first imaged in human volunteers by positron emission tomography (PET) in 1984. Now, quantitative PET imaging of the major opioid receptor types (μ, δ, κ) is possible in the brain and peripheral organs of healthy persons and patient populations. Radioligands are under development for single photon emission computed tomography (SPECT) of opioid receptors as well. These functional, nuclear imaging techniques can trace the fate of radiolabeled molecules directly, but non-invasively, and allow precise pharmacokinetic and pharmacodynamic measurements. Molecular imaging provides unique data that can aid in selecting the best drug candidates, determining optimal dosing regimens, clearing regulatory hurdles and lowering risks of failure. Using a historical perspective, this review touches on opioid receptors as drug targets, and focuses on the status and use of radiotracers for opioid receptor PET and SPECT. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development.

Sigma receptors have been implicated in a myriad of cellular functions, biological processes and diseases. While the precise biological functions of sigma receptors have not been elucidated, recent work has shed some light on to these enigmatic systems. Sigma receptors have recently been a target of drug development related to psychiatric and neurological disorders. Sigma ligands have also been shown to modulate endothelial cell proliferation and can control angiogenesis which makes them a promising target for oncology applications. Other areas currently being investigated include treatment of gastrointestinal, cardiovascular, endocrine and immune system disorders. Of interest is that the human sigma-1 receptor gene contains a steroid binding component, and several gonadal steroids, including progesterone, testosterone and dehydroepiandrosterone (DHEA), interact with sigma-1 receptors. Of the steroids examined thus far, progesterone binds with the highest affinity to human sigma-1 receptors, with a reported affinity (Ki) as high as 30 nM while the other steroids exhibit lower affinity. For this and other reasons, sigma-1 receptors have been proposed as a link between the central nervous system and the endocrine and reproductive systems. Taken together, the above information highlights an important yet largely unexplored but promising area of research to examine the biological function and therapeutic potential of sigma receptors. This review provides an overview of the current knowledge of these sites with a focus on specific areas where in vivo sigma receptor imaging is currently being investigated.

Asthma and chronic obstructive pulmonary disease (COPD) are the 2 most prevalent chronic airway diseases. Much of the morbidity, mortality and health care costs of the diseases are associated with acute exacerbations, which are episodes of increased symptoms and airflow obstruction. Over the last decade evidence has emerged implicating virus respiratory tract infections as a major cause of exacerbations of both asthma and COPD. Current therapies are not very effective in the prevention or treatment of virus-induced exacerbations and exacerbations are therefore a major unmet medical need. The development of new and novel treatments requires a better understanding of the molecular and cellular mechanisms linking virus infection with exacerbations of asthma and COPD. This article provides an overview of current knowledge regarding the mechanisms of virus-induced exacerbations in both asthma and COPD. It will also review existing treatments and future treatments that are in advanced stages of development.

The final aim/target of Pharmaceutical Sciences is to design successful dosage forms for effective therapy, considering individual patient needs and compliance. Development of new drug entities, particularly using peptides and proteins, is growing in importance and attracting increased interest, as they are specifically effective at a comparably low dose. These very potent and specific peptides and proteins can now be produced in large quantities due to increased knowledge and advancements in biotechnological and pharmaceutical applications. A number of peptide and protein products are now available on the market, and numerous studies investigating them have been published in the literature. Although many peptide/protein like products are generally designed for parenteral administration, some other noninvasive routes have also been used. For example, desmopressin is delivered nasally and deoxyribonuclease by inhalation. Although peptides and proteins are generally orally inactive, cyclosporine is an exception. In order to design and develop long-acting, more effective peptide/protein drugs, the controlled release mechanisms and effective parameters need to be understood and clarified. Therefore, we review herein various peptide/protein delivery systems, including biodegradable and nondegradable microspheres, microcapsules, nanocapsules, injectable implants, diffusion- controlled hydrogels and other hydrophilic systems, microemulsions and multiple emulsions, and the use of iontophoresis or electroporation, and discuss the results of recent researches.

It has long been known that the major irreversible toxicity of aminoglycosides is ototoxicity. Among them, streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrosterptomycin, and kanamicin are primarily cochleotoxic. Cochlear damage can produce permanent hearing loss, and damage to the vestibular apparatus results in dizziness, ataxia, and/or nystagmus. Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss. Two mutations in the mitochondrial 12S ribosomal RNA gene have been previously reported to predispose carriers to aminoglycosideinduced ototoxicity. As aminoglycosides are indispensable agents both in the treatment of infections and Meniere’s disease, a great effort has been made to develop strategies to prevent aminoglycoside ototoxicity. Anti-free radical agents, such as salicylate, have been shown to attenuate the ototoxic effects of aminoglycosides. In this paper, incidence, predisposition, mechanism, and prevention of aminoglycoside-induced ototoxicity is discussed in the light of literature data.